4.1 Field of the Invention
The present invention relates to pharmaceutical compositions in the form of a gel for controlled- or sustained-release of a pharmaceutically active agent and to methods for treating or preventing a condition in an animal by administering to an animal in need thereof the pharmaceutical compositions. One particular type of condition for which the pharmaceutical compositions are useful is a microbial infection, e.g., of the skin, ear, or eye, especially for veterinary applications.
4.2 Description of Related Art
It is often desirable to administer drugs using controlled- or sustained-release formulations that can maintain at least a minimum therapeutic level, for example, a blood level, of the drug over extended periods of time. These controlled- or sustained-release formulations reduce the frequency of dosing, for enhanced convenience and compliance, and also reduce the severity and frequency of side effects. For example, by maintaining substantially constant blood levels and avoiding blood level fluctuations of the drug, such as are associated with conventional immediate release formulations that are administered several times a day, controlled- or sustained-release formulations can provide a better therapeutic profile than is obtainable with conventional immediate release formulations.
Known methods for controlled- or sustained-drug release include implanted devices, such as osmotic pumps, and drug dispersed in a biocompatible polymer matrix, which can be implanted, administered orally, or injected. Examples of biocompatible polymers used in such applications include poly(lactic acid) and poly(lactic acid-co-glycolic acid). The polymer typically undergoes slow hydrolysis in vivo to continually release the entrapped drug over time. The polymer degradation products are non-toxic and absorbed or metabolized by the body. For example, when the biocompatible polymer is poly(lactic acid) or poly(lactic acid-co-glycolic acid), the degradation products are the parent acids, lactic acid and glycolic acid, which are absorbed by the body.
The following patents are representative of those that discuss controlled- or sustained-drug release formulations.
U.S. Pat. No. 4,814,173 to Song et al. discloses a transmembranal pharmaceutical preparation for administering a drug to a mammal comprising a medical grade polysiloxane, a catalyst capable of forming an elastomer, a permeation enhancer, and a biologically active material. The patent disclosure focuses most on transdermal drug delivery systems, particularly transdermal patches.
U.S. Pat. No. 5,480,649 to Akazawa et al. discloses a procaterol-containing preparation for application to the skin having a drug-containing layer provided on a support and comprising a substantially water-free adhesive gel base having as essential components polyacrylic acid, a crosslinking agent, at least one lower alcohol or polyvalent alcohol, and 0.1 to 5% by weight of procaterol or a pharmaceutically acceptable salt thereof.
International Publication No. WO 03/034988 discloses compositions of a salt of a pharmacologically active compound and a lipophilic counterion and a pharmaceutically acceptable water soluble solvent that are combined together to provide an injectable composition. When injected into an animal, at least a part of the composition precipitates to form a depot that slowly releases the pharmacologically active compound over time.
The following patents are representative of those that discuss topical or otic pharmaceutical compositions.
U.S. Pat. No. 4,843,096 to Stiefel discloses a topical treatment for inflammatory acne using a non-aqueous gel containing 13-cis-retinoic acid. The patent disclosure indicates a preferred gel formulation containing about 0.05 wt % 13-cis-retinoic acid, 3 wt % hydroxypropyl cellulose, about 96.9 wt % ethanol (SDA-40B), and 0.05 wt % butylated hydroxytoluene.
U.S. Pat. No. 4,847,267 to Deckner et al. discloses a skin treatment composition and method for inhibiting free radicals in the skin comprising 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and/or 6-ethoxy-1,2-dihydro-2,2,4-trimethyl quinoline, and optionally a stabilizer of monoethanolamine sulfite or sodium bisulfite. The skin treatment composition also includes water, at least one preservative, preferably, at least one humectant, at least one emulsifier and/or thickener, and optionally may contain one or more chelating agents, one or more gelling agents, one or more emollients, one or more solvents for the free radical inhibitor or deactivator, one or more sunscreen agents, one or more fragrances, and/or one or more coloring agents.
U.S. Pat. No. 5,110,809 to Wang et al. discloses a stable anhydrous gel formulations for topical antifungal use containing an imidazole, a steroid, a co-solvent system comprising monohydric and dihydric alcohols, and a hydroxyalkylcellulose gellant.
International Publication No. WO 00/09117 discloses topical pharmaceutical compositions containing nimesulfide, a non-steroidal anti-inflammatory agent having poor solubility in water.
U.S. Pat. No. 6,146,664 to Siddiqui discloses stable compositions of ascorbic acid in a non-aqueous or substantially anhydrous silicone vehicle containing substantially no environmental oxygen. The ascorbic acid is present as insoluble particles in the polyorganosiloxane vehicle and has a high degree of bioavailability and effectiveness, for example in topical applications to reduce wrinkles and increase collagen growth and elasticity.
U.S. Pat. No. 6,214,339 to Pellico discloses a treatment for otitis externa in cats and dogs that comprises administering a substantially non-aqueous, di-enzymatic therapeutic composition, in a liquid or gel fluid carrier. An illustrative composition contains glucose, glucose oxidase, potassium iodide, and lactoperoxidase in a fluid mixture of glycerol and propylene glycol.
U.S. Pat. No. 6,238,683 to Burnett et al. discloses anhydrous compositions for topical delivery of a medicament comprising (A) a penetration enhancer of alcohol and/or propylene glycol, (B) a humectant/solvent of polyethylene glycol, glycerin, sorbitol, and/or xylitol, (C) an anhydrous vehicle, and (D) a medicament.
The following patents are representative of those that discuss drug-containing compositions that are non-aqueous and/or gelatinous.
European Patent No. 0 081 896 B1 discloses a waterless thixotropic medicament formulation for administration to animals, especially stable semi-solid formulations of macrolide antibiotics. An exemplary formulation in an essentially anhydrous gel formulation comprising from 0.5-10 wt % of a drug, from 2-25 wt % of a hydroxylated fatty acid ester of glycerin, from 55-97.2 wt % of a glycol or glycerin, and from 0.3-15 wt % of a water-soluble polymer.
U.S. Pat. No. 4,837,008 to Rudy et al. discloses a non-aqueous paste or gel dentrifice composition for periodontal applications comprising a water-soluble, non-aqueous vehicle having dispersed therein an orally acceptable organic or inorganic peroxide and a bicarbonate salt.
U.S. Pat. No. 4,837,213 to Caron et al. discloses a pharmaceutical vehicle for administering and protecting active substances in the form of an anhydrous gel having a viscosity of at least 540 cps and comprising paraffin oil, at least one fatty acid alkyl ester, and a polyvinyldimethyl siloxane-type elastomeric silicone as a thickener.
International Publication No. WO 98/36776 and U.S. Pat. No. 6,669,958 to Trager et al. both disclose methods and compositions for the treatment of a host suffering from a cellular proliferative disease, wherein antiproliferative agents are administered in a substantially non-aqueous gel vehicle comprising at least one polar solvent in combination with one or more thickening agents.
U.S. Pat. No. 6,018,033 to Chen et al. discloses hydrophilic, hydrophobic, and thermoreversible polysaccharide gels, including hydrogels, for controlled drug delivery. Exemplary gel components copolymers of saccharose and a (meth)acrylate or of sucrose or a modified sucrose and hydrophobic poly(alkylene oxide) (meth)acrylates. The sucrose can be modified: by reaction of the sucrose with an epoxy acrylate to form a hydrophilic sucrose; by reaction first with methacryloyl chloride and then with acetyl chloride to form a hydrophobic sucrose; or by reaction first with methacryloyl chloride and then with aminocarboxylic acids to form a thermoreversible sucrose.
U.S. Pat. No. 6,436,455 to Hei et al. discloses antimicrobial and antiviral compositions containing an oxidizing species that is a reaction product of the combination of a quaternary or protonizable nitrogen compound, an oxidant compound, and a halide source at controlled proportions in an in situ aqueous, non-aqueous, gel, aerosol, solid-phase, or powdered preparation.
U.S. patent application No. US 2004/0197408 discloses formulations of a diblock copolymer having a hydrophobic block and hydrophilic block, an additive selected from an amino acid, and an oligopeptide. The formulations, when admixed with water, form drug delivery vehicles in micellar form.
There remains a need in the art, however, for drug-containing pharmaceutical compositions, suitable for topical, otic, and ophthalmic applications, that provide controlled- and/or sustained-release of the drug contained therein.
Citation of any reference in Section 4 of this application is not to be construed that such reference is prior art to the present application.